Catastrophic Pulmonary Vasoconstriction Research Articles

The Toxicokinetic Profile of Dex40-GTMAC3-a Novel Polysaccharide Candidate for Reversal of Unfractionated Heparin.

Though protamine sulfate is the only approved antidote of unfractionated heparin (UFH), yet may produce life threatening side effects such as systemic hypotension, catastrophic pulmonary vasoconstriction or allergic reactions. We have described 40 kDa dextrans (Dex40) substituted with glycidyltrimethylammonium chloride (GTMAC) as effective, immunogenically and hemodynamically neutral inhibitors of UFH. The aim of the present study was to evaluate in mice and rats toxicokinetic profile of the most promising polymer—Dex40-GTMAC3. Polymer was rapidly eliminated with a half-time of 12.5 ± 3.0 min in Wistar rats, and was mainly distributed to the kidneys and liver in mice. The safety studies included the measurement of blood count and blood biochemistry, erythrocyte osmotic fragility and the evaluation of the histological alterations in kidneys, liver and lungs of mice and rats in acute and chronic experiments. We found that Dex40-GTMAC3 is not only effective but also very well tolerated. Additionally, we found that protamine may cause overt hemolysis with appearance of permanent changes in the liver and kidneys. In summary, fast renal clearance behavior and generally low tissue accumulation of Dex40-GTMAC3 is likely to contribute to its superior to protamine biocompatibility. Intravenous administration of therapeutic doses to living animals does not result in the immunogenic, hemodynamic, blood, and organ toxicity. Dex40-GTMAC3 seems to be a promising effective and safe candidate for further clinical development as new UFH reversal agent.

A Case of Catastrophic Pulmonary Vasoconstriction After Protamine Administration in Cardiac Surgery: Role of Intraoperative Transesophageal Echocardiography

A Case of Catastrophic Pulmonary Vasoconstriction After Protamine Administration in Cardiac Surgery: Role of Intraoperative Transesophageal Echocardiography

Inhaled amyl nitrite effectively reverses acute catastrophic thromboxane-mediated pulmonary hypertension in pigs

Acute catastrophic pulmonary vasoconstriction frequently leads to cardiovascular collapse. Rapid and selective pulmonary vasodilation is desired in order to restore haemodynamic stability. This pilot study examined the effectiveness of inhaled amyl nitrite as a selective pulmonary vasodilator. Nine adult swine were anaesthetized. Acute pulmonary hypertension with haemodynamic collapse was induced with a bolus administration of a thromboxane analogue, U46619. Six animals then received a capsule of amyl nitrite. The administration of inhaled amyl nitrite decreased mean pulmonary artery pressure from 42 +/- 3 to 22 +/ 3 mmHg at five minutes (p < 0.05), with a concomitant increase in cardiac output and mean arterial pressure. Pulmonary vascular resistance decreased from 4889 +/- 1338 to 380 +/- 195 dyne. sec. cm(-5) (by 92% from the maximal pulmonary hypertension change), with significant improvement in systemic haemodynamics. During acute thromboxane-mediated pulmonary hypertension with cardiovascular collapse, prompt administration of inhaled amyl nitrite was effective in restoring pulmonary and systemic haemodynamics within five minutes.

Catastrophic Cardiovascular Adverse Reactions to Protamine Are Nitric Oxide/Cyclic Guanosine Monophosphate Dependent and Endothelium Mediated: Should Methylene Blue Be the Treatment of Choice?

Clinical and experimental observations prove that heparin-neutralizing doses of protamine increase pulmonary artery pressures and decrease systemic BP. Protamine also increases myocardial oxygen consumption, cardiac output, and heart rate, and decreases systemic vascular resistance. These cardiovascular effects have clinical consequences that have justified studies in this area. Protamine adverse reactions usually have three different categories: systemic hypotension, anaphylactoid reactions, and catastrophic pulmonary vasoconstriction. The precise mechanism that explains protamine-mediated systemic hypotension is unknown. Four experimental protocols performed at Mayo Clinic, Rochester, MN, studied the intrinsic mechanism of protamine vasodilation. The first study reported in vitro systemic and coronary vasodilation after protamine infusion. The second in vitro study suggested that the pulmonary circulation is extensively involved in the protamine-mediated effects on endothelial function. The third study, carried out in anesthetized dogs, reported the methylene blue and nitric oxide synthase blockers neutralization of the protamine vasodilatatory effects. The fourth study suggested that protamine also causes endothelium-dependent vasodilation in heart microvessels and conductance arteries by different mechanisms including hyperpolarization. Reviewing these experimental results and our clinical experience, we suggest methylene blue as a novel approach to prevent and treat hemodynamic complications caused by the use of protamine after cardiopulmonary bypass. In the absence of prospective clinical trials, a growing body of cumulative clinical evidence suggests that methylene blue may be strongly considered as a therapeutic approach in the treatment of distributive shock.

Warren Zapol: true-life adventures in science, medicine, and innovation: recipient of the 1999 Excellence in Research Award.

Warren Zapol: true-life adventures in science, medicine, and innovation: recipient of the 1999 Excellence in Research Award.

The Use of Nitric Oxide for Managing Catastrophic Pulmonary Vasoconstriction Arising from Protamine Administration

The Use of Nitric Oxide for Managing Catastrophic Pulmonary Vasoconstriction Arising from Protamine Administration

Protamine induces endothelium-dependent vasodilatation of the pulmonary artery

Protamine sulfate, which is used for heparin neutralization, has been reported to induce catastrophic pulmonary vasoconstriction after infusion. However, in the systemic circulation, protamine infusion induces hypotension due to peripheral vasodilation. To determine whether protamine also could induce vasodilation in the pulmonary circulation, third-order canine pulmonary artery segments were studied in vitro in organ chambers. In pulmonary artery segments that were caused to contract with phenylephrine (10(-5) mol/L), protamine sulfate (40 to 400 micrograms/mL, final organ bath concentration) produced concentration-dependent relaxation in canine pulmonary artery segments with endothelium (to 74% +/- 7% of the initial contraction to phenylephrine) that was significantly greater (p < 0.05) than in segments without endothelium (30% +/- 6% of the initial phenylephrine contraction). Pretreatment of arterial segments with NG-monomethyl-L-arginine (10(-5) mol/L), the competitive inhibitor of nitric oxide synthesis from L-arginine, did not change tension of arterial segments, but NG-monomethyl-L-arginine attenuated the relaxation to protamine. The inhibitory effect of NG-monomethyl-L-arginine could be reversed by the addition of L-arginine (10(-4) mol/L) but not D-arginine (10(-4) mol/L). Endothelium-dependent vasodilation to protamine (40 to 400 micrograms/mL) also could be inhibited by heparin (8 U/mL, final organ bath concentration). However, the inhibitory effect of heparin could be overcome by adding higher concentrations of protamine. Protamine-mediated pulmonary vasodilatation could be an important mechanism to protect against the constrictive effects of autocoids generated during heparin neutralization. Such a mechanism might be dysfunctional in certain persons and put them at risk for pulmonary vasoconstriction after protamine infusion.

Catastrophic vasoconstriction after protamine reversal of heparin anticoagulation in the goat.

Catastrophic pulmonary vasoconstriction after protamine reversal of heparin anticoagulation was observed frequently in goats that underwent centrifugal biventricular bypass pump implant. Care should be taken when protamine is used to reverse heparin anticoagulation in goats.

Reversal of protamine-induced catastrophic pulmonary vasoconstriction by prostaglandin E 1

A case of catastrophic pulmonary vasoconstriction occurring after cardiopulmonary bypass after protamine reversal of heparin treated successfully with intravenous prostaglandin E 1 is reported. Systemic hypotension was counteracted by epinephrine given through the left atrium. Protamine-heparin reactions are reviewed and a pathophysiological mechanism for the beneficial effect seen with prostaglandin E 1 is proposed.

Adverse Reactions to Protamine

Adverse responses to protamine are most likely multifactorial in nature. Mechanisms include immune-mediated anaphylaxis, complement-mediated and non-complement-mediated anaphylactoid reactions, and catastrophic pulmonary vasoconstriction. Some patients may be at higher risk for an adverse reaction to protamine. Whereas patient historical data may influence the decision to administer protamine, once administration is decided on all patients should receive protamine in a cautious manner. Rechallenge may be hazardous, but has occurred without problem in some patients.

Catastrophic Pulmonary Vasoconstriction Associated with Protamine Reversal of Heparin

LOWENSTEIN, E.; JOHNSTON, W. E.; LAPPAS, D. G.; D'AMBRA, M. N.; SCHNEIDER, R. C.; DAGGETT, W. M.; AKINS, C. W.; PHILBIN, D. M. Author Information